The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to Applicants’ amendments/remarks received September 24, 2026.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 2-3, 5-6, 8, 15-16, 18 are canceled. Claims 14, 17, 19-23 are withdrawn. Claims 1, 4, 7, 9-13, 24-27, to cancer, Granzyme B, are under consideration.
Priority: This application is a CON of U.S. Application 16859881, filed April 27, 2020, now U.S. Patent 12338483, which claims benefit to provisional application 62/811619, filed February 28, 2019.
Objections and Rejections
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, 7, 9-13, 24-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 and the dependent claims are to a method for determining protease activity in a biological sample, comprising: providing the biological sample with a protease activity sensor comprising a first protease substrate and a second protease substrate; wherein the first substrate is cleaved by a first protease and the second substrate is cleaved by a second protease, and wherein the protease activity sensor provides a detectable signal when both the first substrate and the second substrate are cleaved; detecting the presence of the detectable signal in the sample; and identifying the activity of the first protease and second protease based on the presence of the detectable signal in the sample.
The components and/or elements of the sensor are defined through their activities only and do not require any particular structure. The recited genera of protease substrates, proteases, protease sensors, reporter molecules are defined through their activity only and do not require any particular structure.
The specification discloses a representative species of a sensor that senses the specific proteases Granzyme B (Gzm B) and thrombin (Thrb), where the sensor is designed to emit fluorescent reporters (5-FAM) after cleavage of both protease substrates (at least example 1). Other than the representative species of the specific protease sensors, the specification fails to disclose any other protease substrates, proteases, protease sensors, reporter molecules, and combinations thereof, all being unlimited in structure. The skilled artisan cannot necessarily envision the detailed structures of ALL the variant protease enzymes, substrates, protease sensors, reporter molecules, and combinations thereof, all having no particular structure, that successfully detect and/or identify any protease activity in any biological sample because the specification provides no guidance as to which structural features are essential and critical to have and form protease sensors comprising which protease substrates and are recognized by which proteases, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the methods of making the claimed invention. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating or making it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive.
Applicants assert that the claimed protease activity sensors can detect activity of any two proteases for which the activity sensor includes corresponding protease substrates. Applicants assert that in general, protease-protease substrates are known in the art, see for example Kwong et al. Fig. 2B and Mac et al. supplemental Table 1.
Applicants’ remarks are not persuasive. The proteases and protease substrates disclosed in Kwong et al. and Mac et al. are to specific proteases and protease substrate combinations in specific samples.
As noted above, adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating or making it.
The components and/or elements of the claimed sensor are defined through their activities only and do not require any particular structure. The recited genera of protease substrates, proteases, protease sensors, reporter molecules are defined through their activity only and do not require any particular structure.
While the relevance of proteases and their substrates as clinical targets are studied, only a limited knowledge of protease substrates is currently available (Bhagwat et al. p. 1). Of the 570 known human proteases or 1088 known and putative proteases, only a few have been investigated, thereby, offering a scope for research in this area (Bhagwat et al. p. 1). Study of protease cleavage events and identification of protease substrates is a complicated and time-consuming task and necessitates a well-equipped laboratory with specialized equipment. Also, high-throughput proteomics techniques are often limited to isolation and identification of abundant proteins in complex protein mixtures. This impedes the process of complete characterization of most of the enzymes (Bhagwat et al. p. 13).
The skilled artisan cannot necessarily envision the detailed structures of ALL the variant protease enzymes, substrates, protease sensors, reporter molecules, and combinations thereof, all having no particular structure, that successfully detect and/or identify any protease activity in any biological sample because the specification provides no guidance as to which structural features are essential and critical to have and form protease sensors comprising which protease substrates and are recognized by which proteases, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the methods of making the claimed invention. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating or making it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
For at least these reasons, the 112(a) rejection is maintained.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4, 7, 9-13, 24-27 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 has been amended to recite a method for determining protease activity in a subject comprising providing the subject with a scaffold conjugated with a plurality of protease activity sensors, etc. Claim 1 is indefinite and/or confusing because it is not clear what is meant by “providing” the subject with the scaffold conjugated with the plurality of protease activity sensors. It is not clear how a biological sample obtained from the subject can be detected for a signal and/or protease activity by just providing (i.e. supplying) a subject with the noted scaffold. Further clarification and/or correction is requested.
Claims 4, 7, 9-13, 24-27 are included in this rejection because they are dependent on the above claim and fail to cure its defects.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 4, 7, 9-11, 13, 24-27 are rejected under 35 U.S.C. 103 as being unpatentable over Rajopadhye et al. (US 9999687; previously cited). Rajopadhye et al. disclose imaging agents comprising an enzymatically cleavable oligopeptide linked to either two fluorophores or one fluorophore and one quencher, where the agent is activated by proteases (at least col. 1 lines 19-61). Rajopadhye et al. disclose the imaging agents quickly distribute through the tissues or body fluid of a subject, which allows the agent to travel to tissues or cells for activation by proteases, binding to cell surface receptors or internalization within cells (at least col. 1 lines 29-33). Rajopadhye et al. disclose providing an in vitro method comprising contacting a biological sample with any one or more of the imaging agents; allowing the agent to bind to or associate with a biological target; and detecting a signal emitted from the fluorophore to determine whether the agent has been activated by or bound to the biological target (at least col. 5 lines 57-64). Rajopadhye et al. disclose an exemplary cyclic imaging agent that comprises two fluorophores separated by two peptides; each peptide contains a proteolytic cleavage site where, when intact, the imaging agent is quenched and when the peptides are cleaved by exposure to one or more proteases, at least one fluorophore is no longer quenched by the other (at least col. 6 lines 53-58, also Fig. 10). Rajopadhye et al. disclose the enzymatically cleavable oligopeptide is cleavable by at least one enzyme selected from among metalloproteases, serine proteases, and viral enzymes, etc. (at least col. 45 lines 4-14). Therefore, Rajopadhye et al. can be deemed to disclose two protease substrates (peptide substrates) that are different and cleaved by different proteases.
Rajopadhye et al. disclose an exemplary cyclic imaging agent that comprises two fluorophores separated by two peptides; each peptide contains a proteolytic cleavage site where, when intact, the imaging agent is quenched and when the peptides are cleaved by exposure to two proteases, each fluorophore is no longer quenched by the other (at least col. 59 lines 8-20).
Rajopadhye et al. disclose the agents are chemically linked to nanoparticles (at least col. 25 lines 41-47), including the nanoparticle with a polymer coating suitable for attaching a plurality of agents (at least col. 25 lines 48-54).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed method for determining protease activity in a subject, comprising: providing the subject with a scaffold (nanoparticle) conjugated with a plurality of protease activity sensors, where each protease activity sensor comprises, a cyclic peptide comprising a first protease substrate, a second protease substrate, and a fluorescent molecule; wherein the first and second protease substrates comprise protease cleavage sites; wherein the first substrate is cleaved by a first protease and the second substrate is cleaved by a second protease, wherein the first protease and the second protease are different proteases, and wherein the protease sensor provides a detectable signal by a reporter (or fluorescent molecule) only when both the first substrate and the second substrate are cleaved, wherein the fluorescent molecule released by the protease cleavage diffuses into circulation and into tissues that can be obtained noninvasively; obtaining a sample from the subject; detecting the presence of the detectable signal in the obtained sample; and identifying the activity of the first protease and second protease based on the presence of the detectable signal in the obtained sample (instant claim 1) in view of the teachings of Rajopadhye et al. The motivation to do so is given by the prior art. Rajopadhye et al. disclose cyclic imaging agents that comprise two fluorophores separated by two peptides; each peptide containing a proteolytic cleavage site where, when intact, the imaging agent is quenched and when the two peptides are cleaved by exposure to two proteases, each fluorophore is no longer quenched by the other (at least col. 59 lines 8-20). Rajopadhye et al. disclose the imaging agents quickly distribute through the tissues or body fluid of a subject, which allows the agent to travel to tissues or cells for activation by proteases, binding to cell surface receptors or internalization within cells (at least col. 1 lines 29-33). Rajopadhye et al. further disclose that the agents are chemically linked to nanoparticles (at least col. 25 lines 41-47), including the nanoparticle with a polymer coating suitable for attaching a plurality of agents (at least col. 25 lines 48-54). Therefore, it would have been obvious to arrive at the claimed method because Rajopadhye et al. disclose protease activity sensors comprising the same features recited and used for the same purpose recited, i.e. a method for determining protease activity in a biological sample where the imaging agent travels to the tissues or cells in the biological sample, where two peptides substrates are cleaved by exposure to two proteases to provide a detectable signal.
Regarding instant claim 4, Rajopadhye et al. disclose the imaging agents comprise an enzymatically cleavable oligopeptide linked to either two fluorophores or one fluorophore and one quencher, where the agent is activated by proteases (at least col. 1 lines 19-61), including an exemplary cyclic imaging agent that comprises two fluorophores separated by two peptides; each peptide contains a proteolytic cleavage site where, when intact, the imaging agent is quenched and when the peptides are cleaved by exposure to one or more proteases, at least one fluorophore is no longer quenched by the other (at least col. 6 lines 53-58).
Regarding instant claim 7, as noted above, Rajopadhye et al. disclose that the agents are chemically linked to nanoparticles (at least col. 25 lines 41-47), including the nanoparticle with a polymer coating suitable for attaching a plurality of agents (at least col. 25 lines 48-54).
Regarding instant claims 9-11, Rajopadhye et al. disclose the methods and compositions comprising the agents can be used to help a physician or surgeon identify and characterize areas of disease (at least col. 68 lines 33-45), including cancer (at least col. 68 line 62).
Regarding instant claim 13, Rajopadhye et al. disclose the enzymatically cleavable oligopeptide is cleavable by at least one enzyme selected from among metalloproteases, serine proteases, and viral enzymes, etc. (at least col. 45 lines 4-14).
Regarding instant claims 24-25, Rajopadhye et al. disclose that the imaging agents can be rendered to favor a particular route of excretion, i.e. through the kidneys rather than liver (at least col. 29 lines 29-47) and that the methods of the invention can be used to determine a number of indicia, including tracking the localization of the agent in the subject over time or assessing changes or alterations in the metabolism and/or excretion of the agent in the subject over time (at least col. 68 lines 22-26). Therefore, it would be obvious that the sample obtained from the subject for detecting the presence of the detectable signal in the obtained sample; and identifying the activity of the first protease and second protease based on the presence of the detectable signal in the obtained sample is a urine sample.
Regarding instant claims 26-27, Rajopadhye et al. disclose the imaging agents comprise an enzymatically cleavable oligopeptide linked to either two fluorophores or one fluorophore and one quencher, where the agent is activated by proteases (at least col. 1 lines 19-61), including an exemplary cyclic imaging agent that comprises two fluorophores separated by two peptides; each peptide contains a proteolytic cleavage site where, when intact, the imaging agent is quenched and when the peptides are cleaved by exposure to one or more proteases, at least one fluorophore is no longer quenched by the other (at least col. 6 lines 53-58, also Fig. 10). Additionally, Rajopadhye et al. disclose that the agents are chemically linked to nanoparticles (at least col. 25 lines 41-47), including the nanoparticle with a polymer coating suitable for attaching a plurality of agents (at least col. 25 lines 48-54). It would be obvious that Rajopadhye et al. reasonably disclose the fluorophore is conjugated to the cyclic peptide between a first end of the first proteolytic cleavage site and a first end of the second proteolytic cleavage site; therefore, it would be obvious to conjugate or chemically link the agent(s) to the nanoparticle between a second end of the first proteolytic cleavage site and a second end of the second proteolytic cleavage site and where a quencher is also conjugated to the cyclic peptide between a second end of the first proteolytic cleavage site and a second end of the second proteolytic cleavage site.
Reply: In view of Applicants’ amendments/remarks, the previous 102(a)(2) rejection as being anticipated by Rajopadhye et al. has been withdrawn. However, the claims remain unpatentable under a new 103 rejection over Rajopadhye et al. for the reasons noted above and herein.
Applicants assert that Rajopadhye et al. do not disclose or suggest a method where the imaging agent and biological sample come into contact in vivo and the biological sample is removed from the subject and imaged in vitro.
Applicants’ remarks are not persuasive. As previously noted, Rajopadhye et al. disclose the imaging agents quickly distribute through the tissues or body fluid of a subject, which allows the agent to travel to tissues or cells for activation by proteases, binding to cell surface receptors or internalization within cells (at least col. 1 lines 29-33). Rajopadhye et al. disclose providing an in vitro method comprising contacting a biological sample with any one or more of the imaging agents; allowing the agent to bind to or associate with a biological target; and detecting a signal emitted from the fluorophore to determine whether the agent has been activated by or bound to the biological target (at least col. 5 lines 57-64). Rajopadhye et al. also disclose that the imaging agents can be rendered to favor a particular route of excretion, i.e. through the kidneys rather than liver (at least col. 29 lines 29-47) and that the methods of the invention can be used to determine a number of indicia, including tracking the localization of the agent in the subject over time or assessing changes or alterations in the metabolism and/or excretion of the agent in the subject over time (at least col. 68 lines 22-26).
Therefore, Rajopadhye et al. fairly disclose that the imaging agent and biological sample come into contact in vivo and the biological sample is removed from the subject and detected in vitro.
Applicants assert that Rajopadhye et al. do not disclose a plurality of protease activity sensors conjugated to a scaffold as presently claimed. Applicants assert that in Rajopadhye et al., at col. 25 lines 48-54, the nanoparticle is considered to be part of the imaging agent, rather than the imaging agents being conjugated to the nanoparticle as presently claimed.
Applicants’ remarks are not persuasive. As noted above, Rajopadhye et al. disclose the imaging agents comprise an enzymatically cleavable oligopeptide linked to either two fluorophores or one fluorophore and one quencher, where the agent is activated by proteases (at least col. 1 lines 19-61), including an exemplary cyclic imaging agent that comprises two fluorophores separated by two peptides; each peptide contains a proteolytic cleavage site where, when intact, the imaging agent is quenched and when the peptides are cleaved by exposure to one or more proteases, at least one fluorophore is no longer quenched by the other (at least col. 6 lines 53-58, also Fig. 10).
Therefore, Rajopadhye et al. disclose protease activity sensors (agents of Rajopadhye et al.) comprising the same features recited and used for the same purpose recited, i.e. a method for determining protease activity in a biological sample where the imaging agent travels to the tissues or cells in the biological sample, where two peptides substrates are cleaved by exposure to two proteases to provide a detectable signal.
Rajopadhye et al. further discloses that the imaging agents (plural) are chemically linked to nanoparticles that are either fluorescent or non-fluorescent and can be used in a variety of in vitro and in vivo applications (at least col. 25 lines 41-47). Therefore, Rajopadhye et al. already contemplate conjugating a plurality of the imaging agents to a nanoparticle (or scaffold).
Additionally, as also noted by Applicants, at col. 25 lines 48-54, Rajopadhye et al. disclose that the imaging agents can include a fluorescent and/or non-fluorescent superparamagnetic metal oxide nanoparticle with one or more of the following features: (1) a polymer coating suitable for attaching a plurality of agents (2) a non-crosslinked polymer coating suitable for attaching from about 10 to about 300 agents per particle, and (3) a polymer coating that is amenable to efficient chemical linking of the agents with retention of their biological properties to yield molecular imaging agents. The agent modified metal oxide nanoparticle can be a highly stable molecular imaging agent in vitro, both before and after chemical linking of the agents, but yet are labile and/or degradable in vivo.
Therefore, while Rajopadhye et al. disclose that the imaging agents “include” a nanoparticle, it is still expressly disclosed in Rajopadhye et al. that the nanoparticle is amenable to efficient chemical linking of the agents or attaching a plurality of the agents with retention of their biological properties to yield molecular imaging agents. Therefore, Rajopadhye et al. still disclose conjugating or attaching a plurality of their agents, which comprise the same features recited and used for the same purpose recited, onto a nanoparticle (or a scaffold).
Regarding Applicants’ remarks that the present application has discovered that surprisingly, conjugating a plurality of protease activity sensors to a scaffold increases valency of presentation (Sivakumar et al.), the remarks are not persuasive. In this instance, Rajopadhye et al. disclose both features recited in the instant claims, cyclic agents and conjugating a plurality of the agents to a nanoparticle. It would also be obvious and not surprising that a plurality of agents results in an increased rate of proteolysis and amplified detectable signal (increased valency of presentation) compared to one agent.
Claims 1, 12 are rejected under 35 U.S.C. 103 as being unpatentable over Rajopadhye et al. (US 9999687; previously cited) in view of Shu et al. (WO 2015154006; previously cited). The teachings of Rajopadhye et al. over at least instant claim 1 are noted above. Rajopadhye et al. disclose the methods and compositions comprising the agents can be used to help a physician or surgeon identify and characterize areas of disease (at least col. 68 lines 33-45). Rajopadhye et al. do not explicitly teach that the one or more proteases (first protease and/or second protease) are promoted by a therapeutic agent.
Shu et al. disclose fluorescent protease reporters (abstract). Shu et al. disclose the activity of a protease can be promoted by a therapeutic agent (at least paragraph 0026).
Regarding instant claim 12, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include a therapeutic agent in the biological sample disclosed in the method of Rajopadhye et al. for detecting or determining protease activity in sample because Shu et al. disclose protease activity can be detected after administration of a therapeutic agent.
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive. The reasons for maintaining Rajopadhye et al. are the same as noted above.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 4, 7, 9-13, 24-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12338483 (‘483) in view of Rajopadhye et al. (supra) and Shu et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘483 patent claims are drawn to a method for determining protease activity in a biological sample from a subject, comprising: providing or contacting the biological sample with a protease activity sensor comprising a first protease substrate and a second protease substrate; wherein the first substrate is cleaved by a first protease and the second substrate is cleaved by a second protease, and wherein the protease activity sensor provides a detectable signal when both the first substrate and the second substrate are cleaved; detecting the presence of the detectable signal in the sample; and identifying the activity of the first protease and second protease based on the presence of the detectable signal in the sample. The ‘483 patent claim 1 differs from the instant claim 1 by not explicitly reciting providing the subject with a scaffold conjugated with a plurality of the protease activity sensors. The components and features recited in the instant claims are also all recited in the ‘483 patent claims. Further, in view of the noted teachings of Rajopadhye et al. above, it would have been obvious to provide the subject with a scaffold conjugated with a plurality of the protease activity sensors before contacting the sample with the protease activity sensor in the ‘483 patent claim because Rajopadhye et al. disclose agents comprising the same features and used for the same purpose as the ‘483 patent claims and the instant claims, i.e. for determining protease activity in a biological sample, are conjugated to nanoparticles and provided to a subject, including tracking the localization of the agent in the subject over time or assessing changes or alterations in the metabolism and/or excretion of the agent in the subject over time.
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive. The reasons for maintaining the nonstatutory double patenting are noted above.
Both the instant claims and the ‘483 patent claims are drawn to a method for determining protease activity in a biological sample from a subject, comprising providing protease activity sensors comprising the same features and used for the same purpose.
The ‘483 patent claim 1 differs from the instant claim 1 by not explicitly reciting providing the subject with a scaffold conjugated with a plurality of the protease activity sensors. However, the components and features recited in the instant claims are also all recited in the ‘483 patent claims.
In view of the noted teachings of Rajopadhye et al. above, it would have been obvious to provide the subject with a scaffold conjugated with a plurality of the protease activity sensors of the ‘483 patent claims before contacting the sample with the protease activity sensor in the ‘483 patent claim because Rajopadhye et al. disclose agents comprising the same features and used for the same purpose as the ‘483 patent claims and the instant claims, i.e. for determining protease activity in a biological sample, are conjugated to nanoparticles and provided to a subject, including tracking the localization of the agent in the subject over time or assessing changes or alterations in the metabolism and/or excretion of the agent in the subject over time.
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Marsha Tsay/Primary Examiner, Art Unit 1656
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